Estrogen Replacement Therapy after Treatment for Endometrial Cancer

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Many women who have undergone bilateral oophorectomy (removal of
the ovaries) as part of their treatment for endometrial cancer have
significant morbidity related to estrogen deprivation. While
vasomotor symptoms (hot flushes) and vaginal atrophy (shrinkage)
leading to dyspareunia (painful sexual intercourse) are very common
and may have a significant impact on a woman's quality of life, they
are not life threatening. Osteoporosis (weakening of the bones) and
an increased risk for development of atherosclerotic cardiovascular
disease (hardening of the arteries) are all a consequence of loss of
estrogen. Osteoporosis may contribute to the risk of hip fractures
in elderly women that is associated with a mortality of up to 24%
within one year of the fracture [1].

Adenocarcinoma of the endometrium is an estrogen-sensitive
neoplasm. Estrogen replacement therapy (ERT) has traditionally been
withheld from women after treatment for endometrial cancer, based on
the belief that it might stimulate any residual tumor cells and
increase the risk for recurrent disease. However, this theory has
never been substantiated, and recent data suggest that ERT is safe in
patients with a history of low-risk endometrial cancer.

Two retrospective studies have examined this issue. In 1986,
Creasman et al. [2] studied 221 patients with Stage I endometrial
cancer (limited to the uterus). A historical control group with a
similar distribution of accepted prognostic factors (substage, tumor
grade, depth of invasion, nodal metastasis, peritoneal cytology, and
hormone receptor status) were compared with a study group receiving
ERT. The estrogen-treated patients used both oral and vaginal
therapy, and the length of ERT ranged from three to 84 months (median
26 months). The interval of time from cancer therapy to initiation of
ERT ranged from zero to 81 months (median interval 15 months). Median
follow-up times after initial therapy for cancer were 60 months in
estrogen users and 42 months in nonestrogen users, and in the first
group, the median follow-up time after ERT was initiated was 32
months. Among the 174 nontreated patients there were 26 recurrences
(14.9%), and in the 47 patients taking ERT there was only one
recurrence (2.1%). Thus, the estrogen-treated group did not have an
increased risk of recurrence. In fact, this group was found to have
significantly longer disease-free survival (p<.05).

In 1990, Lee et al. [3] retrospectively evaluated 143 patients
with Stage I endometrial cancer . Of this group, a subset of 106
patients considered low-risk (grade 1 or 2, <1/2 myometrial
invasion, and no metastases to nodes or other organs) were offered
oral ERT. These patients were followed for at least two years (median
follow-up time after initial cancer therapy was 87 months for
estrogen users and 63 months for nonusers). The majority of the
estrogen users (57%) started estrogen therapy within the first
postoperative year, and had taken estrogen for >5 years (55%) at
the time of data analysis. In the 44 estrogen-treated patients there
were no recurrences and in the 62 other low risk nonestrogen-treated
patients, one recurrence occurred. Again, in these low risk patients,
no increase in recurrence rate was seen in the estrogen-treated
group.

These studies, although small and retrospective, certainly suggest
that ERT is safe in patients with a history of low risk, early stage
endometrial cancer who have completed their cancer therapy. An
American College of Obstetricians and Gynecologists (ACOG) Committee
Opinion concluded that estrogen therapy may be used in patients with
past endometrial cancer, although patient selection must be based on
prognostic indicators [4]. The need for adding progestational agents
to estrogen therapy is unknown, but since progestins are known to
antagonize the growth-promoting effects of estrogen on the
endometrium, progestin addition seems reasonable, at least until
larger, randomized trials are performed. Finally, more information is
needed before recommendations can be made regarding estrogen doses,
mode of estrogen therapy, and best time for initiating ERT after
cancer treatment.

In conclusion, patients who have been treated for endometrial
cancer and fall into a low risk group (stage I disease, grade 1 or 2,
and <1/2 myometrial invasion) have a <5% recurrence rate
regardless of whether or not ERT is given [5, 6]. The long term
benefits of estrogen therapy including cardiovascular protection, a
reduced risk of osteoporosis, and fewer vasomotor and other
menopausal symptoms may outweigh the small risk of disease recurrence
in these patients. In these selected patients, the contribution of
ERT to the risk of recurrence is probably negligible.

4. American College of Obstetricians and Gynecologists, Committee
on Gynecologic Practice. Estrogen replacement therapy and endometrial
cancer. ACOG Committee Opinion No. 126. Washington DC: American
College of Obstetricians and Gynecologists (1993).